Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as
a result of germline mutations in the APC gene. Despite a clear clinical diagnosis
of FAP, a certain proportion of the APC variants are not readily detectable through
conventional genotyping routines. We accomplished genome sequencing in duo of the
disease-affected proband and non-affected sibling followed by in silico predictions
and a series of RNA-based assays clarifying variant functionality. By prioritizing
variants obtained by genome sequencing, we discovered the novel deep intronic alteration
APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of
56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant
splicing event was complete and its splice product was subject to nonsense-mediated
decay. Co-segregation was observed between the variant carrier status and the disease
phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic
variant causative of the disease.
